Impact of COVID-19 pandemic on routine childhood vaccinations.

Routine pediatric vaccination is one of the most effective public health inter-ventions for the control of a number of fatal diseases. However, during the coronavirus disease 2019 pandemic, routine pediatric vaccination rates were severely affected by disruptions of health services and vaccine confidence issues. Governments and the United Nations have taken measures to re-establish routine pediatric vaccination, while additional efforts are needed to catch up and develop plans to ensure routine vaccination services for the future pandemics.

Identification of risk factors and construction of a nomogram predictive model for post-stroke infection in patients with acute ischemic stroke.

BACKGROUND: Post-stroke infection is the most common complication of stroke and poses a huge threat to patients. In addition to prolonging the hospitalization time and increasing the medical burden, post-stroke infection also significantly increases the risk of disease and death. Clarifying the risk factors for post-stroke infection in patients with acute ischemic stroke (AIS) is of great significance. It can guide clinical practice to perform corresponding prevention and control work early, minimizing the risk of stroke-related infections and ensuring favorable disease outcomes. AIM: To explore the risk factors for post-stroke infection in patients with AIS and to construct a nomogram predictive model. METHODS: The clinical data of 206 patients with AIS admitted to our hospital between April 2020 and April 2023 were retrospectively collected. Baseline data and post-stroke infection status of all study subjects were assessed, and the risk factors for post-stroke infection in patients with AIS were analyzed. RESULTS: Totally, 48 patients with AIS developed stroke, with an infection rate of 23.3%. Age, diabetes, disturbance of consciousness, high National Institutes of Health Stroke Scale (NIHSS) score at admission, invasive operation, and chronic obstructive pulmonary disease (COPD) were risk factors for post-stroke infection in patients with AIS (P < 0.05). A nomogram prediction model was constructed with a C-index of 0.891, reflecting the good potential clinical efficacy of the nomogram prediction model. The calibration curve also showed good consistency between the actual observations and nomogram predictions. The area under the receiver operating characteristic curve was 0.891 (95% confidence interval: 0.839-0.942), showing predictive value for post-stroke infection. When the optimal cutoff value was selected, the sensitivity and specificity were 87.5% and 79.7%, respectively. CONCLUSION: Age, diabetes, disturbance of consciousness, NIHSS score at admission, invasive surgery, and COPD are risk factors for post-stroke infection following AIS. The nomogram prediction model established based on these factors exhibits high discrimination and accuracy.

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2.

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.

Genetic variants, haplotype determination, and function of novel alleles of CYP2B6 in a Han Chinese population.

Amino acid variants in protein may result in deleterious effects on enzymatic activity. In this study we investigate the DNA variants on activity of CYP2B6 gene in a Chinese Han population for potential use in precision medicine. All exons in CYP2B6 gene from 1483 Chinese Han adults (Zhejiang province) were sequenced using Sanger sequencing. The effects of nonsynonymous variants on recombinant protein catalytic activity were investigated in vitro with Sf12 system. The haplotype of novel nonsynonymous variants with other single nucleotide variants in the same allele was determined using Nanopore sequencing. Of 38 alleles listed on the Pharmacogene Variation Consortium, we detected 7 previously reported alleles and 18 novel variants, of which 11 nonsynonymous variants showed lower catalytic activity (0.00-0.60) on bupropion compared to CYP2B6*1. Further, these 11 novel star-alleles (CYP2B6*39-49) were assigned by the Pharmacogene Variation Consortium, which may be valuable for pharmacogenetic research and personalized medicine.

Ubiquitinome Analysis Uncovers Alterations in Synaptic Proteins and Glucose Metabolism Enzymes in the Hippocampi of Adolescent Mice Following Cold Exposure.

Cold exposure exerts negative effects on hippocampal nerve development in adolescent mice, but the underlying mechanisms are not fully understood. Given that ubiquitination is essential for neurodevelopmental processes, we attempted to investigate the effects of cold exposure on the hippocampus from the perspective of ubiquitination. By conducting a ubiquitinome analysis, we found that cold exposure caused changes in the ubiquitination levels of a variety of synaptic-associated proteins. We validated changes in postsynaptic density-95 (PSD-95) ubiquitination levels by immunoprecipitation, revealing reductions in both the K48 and K63 polyubiquitination levels of PSD-95. Golgi staining further demonstrated that cold exposure decreased the dendritic-spine density in the CA1 and CA3 regions of the hippocampus. Additionally, bioinformatics analysis revealed that differentially ubiquitinated proteins were enriched in the glycolytic, hypoxia-inducible factor-1 (HIF-1), and 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathways. Protein expression analysis confirmed that cold exposure activated the mammalian target of rapamycin (mTOR)/HIF-1α pathway. We also observed suppression of pyruvate kinase M2 (PKM2) protein levels and the pyruvate kinase (PK) activity induced by cold exposure. Regarding oxidative phosphorylation, a dramatic decrease in mitochondrial respiratory-complex I activity was observed, along with reduced gene expression of the key subunits NADH: ubiquinone oxidoreductase core subunit V1 (Ndufv1) and Ndufv2. In summary, cold exposure negatively affects hippocampal neurodevelopment and causes abnormalities in energy homeostasis within the hippocampus.

Effects of NLRP3 Inflammasome Mediated Pyroptosis on Cardiovascular Diseases and Intervention Mechanism of Chinese Medicine.

Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway is an important mechanism underlying myocardial pyroptosis and plays an important role in inflammatory damage to myocardial tissue in patients with cardiovascular diseases (CVDs), such as diabetic cardiomyopathy, ischemia/reperfusion injury, myocardial infarction, heart failure and hypertension. Noncoding RNAs (ncRNAs) are important regulatory factors. Many Chinese medicine (CM) compounds, including their effective components, can regulate pyroptosis and exert myocardium-protecting effects. The mechanisms underlying this protection include inhibition of inflammasome protein expression, Toll-like receptor 4-NF-κB signal pathway activation, oxidative stress, endoplasmic reticulum stress (ERS), and mixed lineage kinase 3 expression and the regulation of silent information regulator 1. The NLRP3 protein is an important regulatory target for CVD prevention and treatment with CM. Exploring the effects of the interventions mediated by CM and the related mechanisms provides new ideas and perspectives for CVD prevention and treatment.

Digital measuring the ocular morphological parameters of guinea pig eye in vivo with Python.

AIM: To quantitatively measure ocular morphological parameters of guinea pig with Python technology. METHODS: Thirty-six eyeballs of eighteen 3-week-old guinea pigs were measured with keratometer and photographed to obtain the horizontal, coronal, and sagittal planes respectively. The corresponding photo pixels-actual length ratio was acquired by a proportional scale. The edge coordinates were identified artificially by ginput function. Circle and conic curve fitting were applied to fit the contour of the eyeball in the sagittal, coronal and horizontal view. The curvature, curvature radius, eccentricity, tilt angle, corneal diameter, and binocular separation angle were calculated according to the geometric principles. Next, the eyeballs were removed, canny edge detection was applied to identify the contour of eyeball in vitro. The results were compared between in vivo and in vitro. RESULTS: Regarding the corneal curvature and curvature radius on the horizontal and sagittal planes, no significant differences were observed among results in vivo, in vitro, and the keratometer. The horizontal and vertical binocular separation angles were 130.6°±6.39° and 129.8°±9.58° respectively. For the corneal curvature radius and eccentricity in vivo, significant differences were observed between horizontal and vertical planes. CONCLUSION: The Graphical interface window of Python makes up the deficiency of edge detection, which requires too much definition in Matlab. There are significant differences between guinea pig and human beings, such as exotropic eye position, oblique oval eyeball, and obvious discrepancy of binoculus. This study helps evaluate objectively the ocular morphological parameters of small experimental animals in emmetropization research.

Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

The remediation potential and kinetics of Pb2+ adsorbed by the organic frameworks of Cladophora rupestris.

Cladophora rupestris is ubiquitous in many kinds of waterbodies, and C. rupestris biomass can serve as a carrier for adsorbing and transferring heavy metals. Batch experiments and characterization were performed. Results showed that the organic frameworks of C. rupestris (CROF) had a specific surface area of 2.58 m2/g and an external surface area of 2.06 m2/g. Many mesopores were present in CROF, mainly distributed in 2.5-7.5 nm. The zeta potentials were within the range of - 4.46 to - 13.98 mV in the tested pH of 2.0-9.0. CROF could effectively adsorb Pb2+ in large pH range. The maximum adsorption capacity (qmax) of Pb2+ on CROF was 15.02 mg/g, and 97% of Pb2+ was adsorbed onto CROF after 25 min. CROF had a preferential adsorption of Pb2+. The protein secondary structures and carbon skeletons of CROF all worked in adsorption. The main Pb2+ adsorption mechanisms were pore filling, electrostatic attraction, Pb-π interaction, and surface complexation. Therefore, it is valuable as a biosorbent for the removal of Pb2+ from waterbodies.

Seven new pentasaccharides from the roots of Rehmannia glutinosa.

Seven new pentasaccharides (1-7), rehmaglupentasaccharides A-G, were isolated from the air-dried roots of Rehmannia glutinosa. Their structures were established from the spectroscopic data obtained and by chemical evidence. The known verbascose (8) and stachyose (9) were also obtained in the current investigation, and the structure of stachyose was unequivocally defined using X-ray diffraction data. Compounds 1-9 were tested for their cytotoxicity against five human tumor cell lines, influence on dopamine receptor activation, and proliferation effects against Lactobacillus reuteri.